delta 20,21-3,17-dioxy-11-ketopregnenes and process



Patented Dec. 27, 1949 2,492,190

UNITED STATES PATENT OFFICE A -3,17-DIOXY-ll-KETOPREGNENES AND PROCESS Lewis 11. Sarett, Princeton, N. J assiznor to Merck & Co., Inc., Rahway, N. J a corporation of New Jersey No Drawing. Original application July 14, 1945,

Serial No. 605,194. Divided and this application February 23, 1946, Serial No. 649,762

Claims. (Cl. 260-3914),

1 2 This invention is concerned generally with formulae the former configuration is shown by novel chemical compounds of the cyclopentanowriting the C-17 substituent (hydroxyl) to the dixnethylpolyhydrophenanthrene series and to right of the C-l7 carbon side chain. thus processes of preparing same; more particularly CH'OH it relates to novel compounds useful as intermel diates in the synthesis of the adrenal cortical C303 03 hormone A4,5-3,11,20-triketo- 17 (p) ZI-dihydroxy pregnene. This application is a divisional of copending application Ser1a1No.605,194 filed July m the latter above the 51 de chain. thus 14, 1945, now abandoned. 10

This hormone is known to occur naturallyinthe 0H OH CH adrenal cortex; it has the structural formula: X

H 19 200:0 3. The stereochemical relationship of rings A 0 o CHiJL-OH and B is indicated in the formulae by a solid I/"\ line representing the valence bond in the cis conon C13 16011,

C D figuration. 5 g l 15 H In accordance with the present invention it is 1 3 9\ now found this hormone can be synthesized by \l/ g B102 010 80 reactions indicated as follows:

i A I i on. ono= 3 5c 7 H,

\g/ (in-coin cinema I H H: u on. on. (Standard numbering of C-positions) 0\ o\ This formula, for purposes of convenience, is CH :32? H hereinafter reproduced below in the abbreviated form: :0

CHaOH H0 BO cm on I i o\ 36 1 rygi n g CH; c reagent OH. cm

Ii-CON: K-COX 0 on, on.

f In the following description of the invention, MN the stereochemical relationships of substituents CH1 cm are indicated by the following conventions:

1. A substituent at the 0-3 position which is trans to the 0-10 methyl group is parenthetically designated (0;). H0 no 2. A substituent at the C-l7 position, the stereochemical configuration of which is identical with that of the naturally occurring adrenal hormones, is parenthetically designated ([3) the epimeric configuration is designated (a) In the structural iv III 3 i 1 A3103 7 i on on OK 050B CH; cn=cm 'l w a? My I-mo on. H no HOH 80 2? cmx' 0 CH CH CK. 0 I 0 OH on I halogenating agent o R 3 0 XVI xv 03 0mm cn-cmon" O 0 CB 1T0? on I XVII 110 m R RIO hydrolylll no H iO m CH-CHQOH I CH 0 68 RIIIOH O\ (R""):0

v OH on xvm 70 m air) H mam H 1 [oxidation 8,408,190 I p O l err-onion oilonion l on on hydrolon a on xxx xx minim count 08001! $11011 cn-omoa xxx: xxx on on on r h La 1111mm on 2' cn onion xxn xxm o 0 cm on o n a cholanic acid (11) which is treated with an agent capable of converting an organic carboxylic acid deflating O 1 agent 08.0 RU"! 8"". 3o

on on on. on

o v o I In the above formulae. R, R, R", R, R on x" on R'", and R are acyl; X, X and X" are halogen; and M is an alkali metal or an alkaline earth xxv metal/2. The reactions above indicated are conducted as o 0 follows:

. 3-hydroxy-1i-keto-bisnorcholanic acid (1) is acylated producing 3-acyloxy 11 keto bisnor- III" III" Omen to the corresponding acid halide, thus forming 5 the acid halide of S-acvloxy-ll-ketO-bisnorchoon. on on. on lanic acid (111). Upon treatment of this acid 0 o\ halide with an alkali metal azide or alkaline i, earth metal azide, the azide of 3-acyloxy-11-keto- CH- Pyri ine on. bisnorcholanic acid (IV) is formed. Decomposition of this azide with an acidic aqueous solution produces 3-acyloxy-1l-keto 20 aminopreznane (V). 0 0 Upon treatment of this compound (V) with g nitrous acid, a mixture containing predominantly XXVI A 3 acyloxy 11 keto pregnene (VI) and A=-* -3-acyloxy-1l-keto-pregnene (VII) and a xxv 1 minor amount of 3-acyloxy-l1-keto-20-hydroxypregnane (VIII) results. The proportion of the desired compound (VI) present in this mixture 0303' 01mm can be increased by treating the mixture with an non n-on aromatic sulfonvl halide followed by further OH on on treatment with a base to cause removal of the elements of the corresponding aromatic sulfonic 0\ acid. The mixture of these compounds (VI) and cm I 05 (V11) or of (VI), (VII) and (VIII), is then treated with ozone followed by decomposition of the ozonide, producing 3-acyloxy-1Ll7-diketoetiocholane (IX) and 3-acyloxy-11-keto-17-formo 0 yletiocholane (X). Compound (X) is oxidized to 3-acyloxy-11-ketoetiocholanic acid (XI) which is separated from compound (IX) by extraction with alkali.

- Compound (IX) is hydrolyzed to form 3-hy- [mum droiqr-lLl'l-diketoetiocholane (XII) which is 1' treated with acetylene to form 3,17-dihydroxy- 11 keto pregnine 6 (XIII) This compound (XIII) is catalytically hydrogenated to produce a 3,17 dihydroxy 11 ketopregnene (XIV) which is acylated to form d -li-acyloxy- 17-hydroxy-11-ketopregnene (XV) and thiscompound is halogenated to produce d -li-acyloxy- 11-keto-21-halopregnene (XVI). When treated with an alkali metal salt or alkaline earth metal salt of an organic acid, this compound yields A -3,21 diacyloxy l1 ketopregnene (XVII) which is hydrolyzed producing A"--3,21-dihydroxy 11 ketopregnene (XVIII). The latter product (XVIH) is partially esterified and the mono ester (IHX) thus produced is oxidized to convert the unesterified hydroxy group in the 3 position to a keto group, thereby yielding the ester of N -3,11 diketo-21-acyloxy pregnene (XX). This product (XX) is hydrolyzed and the A -3,11 diketo 21 hydroxypregnene (XXI) thus formed is acylated producing A -3,1l-diketo 21 acyloxypregnene (XXII). Hydroxylation at the unsaturation of the last mentioned compound (XXII) results in the production of 3,11 diketo 17 20,21 trihydroxypregnene (XXIII) which is then acylated to form 3,11-diketo-17 (5) -hydroxy-20,21 diacyloxypregnene (XXIV). When brominated, this compound yields 3,11-diketo-4-bromo-17 8) -hydroxy-20,21- diacyloxypregnene (XXV).

This compound is then treated with a reagent capable of removing the elements of hydrogen bromide, thereby producing A -3,l1-diketo- 17(3) -hydroxy-20,2l-diacyloxypregnene (XXVI) which on hydrolysis forms A -3,l1 diketo- 17 8) ,20,21-trihydroxypregnene (XXVII) Partial acylation of this compound (XXVII) gives M -3,11 diketo-17 (,8) ,20 dihydroxy 21 acyloxypregnene (XXVIII) which, when oxidized, yields a mixture of A -3,l1,20-triketo-17(fl)-hydroxy 21 acyloxypregnene (XXIX) and A 3,11,17-triketo androstene (XXX). Compounds (XXIX) and (XXX) may be separated by conventional operations, for example chromatography, and compound (XXIX) hydrolyzed to produce the desired adrenal hormone, n -3,11,20- triketo-17(p) ,2l-dihydroxypregnene.

This invention is concerned with compounds of the type represented by the intermediates 14 and 15 above, and with processes of producing same, which intermediates are represented by the formula droxypregnene which 8 may be represented by the structural formula:

5 I on err-on.

The hydrogenation is preferably carried out at room temperature and under atmospheric pressure in a suitable solvent such as a lower aliphatic alcohol, e. g ethanol, although of course superatmospheric pressures and/ or other temperatures may be employed if desired. The hydrogenation is discontinued after one mole of hydrogen has been absorbed; the triple bond is hydrogenated under the above conditions to yield the desired unsaturated compound.

3 acyloxy ll-keto 17 hydroxypregnine-20 may be hydrogenated using the same catalysts under the same conditions as hereinabove disclosed to produce A -3-acy1oiw-11-keto-l7- hydroxypregnene. The acyl group may be any desired group derived for example from acetic. propionic, butyric, valeric, caproic, capric, etc., benzoic, toluic, or phenylacetic acid. The preferred acyl compounds are those having the radi- 5 cals of the lower aliphatic carboxylic acids, i. e.

those having 6 carbon atoms or less.

The following examples are illustrative of the hydrogenation procedure; it will be understood these examples are for purposes of illustration and that the invention is'not limitedthereto.

Example 1 A suspension of 300 mg. of 2% palladiumbarium carbonate catalyst in 50 cc. of absolute alcohol was shaken with hydrogen until abwrption of hydrogen ceased. To this suspension was then added 658 mg. of 3(a),17(a) -dihydroxy-l1- ke'topregnine-20 and the mixture shaken under hydrogen until one mol of hydrogen was absorbed.

CH! CH=CHg in which R isacyl or hydrogen.-

The starting materials employed in the procaccording to this invention, 3,17-dihydroxylleketopregnine, or a v3-acyl derivative thereof,

may be obtained as described in copending application Serial No. 649,761 filed February 23, 1946.

In accordance with thisinvention the compound 3,17-dihydroxy-ll-ketopregnine-ZO or 3'- 'acyloxy-ll-keto 17 hydroxypregnine-20 is hydrogenated to produce A= -3,17-dihydroxy-11- The 3-monoacetate of the above compound was 1 r prepared by warming the above compound with acetic anhydride and pyridine on the steam bath for 30 minutes. The mixture was diluted with water, extracted with ether, the ether extract washed successively with dilute hydrochloric acid 76 and dilute potassium carbonate solution and coneentrated to dryness. The residue having the structural formula:

1'; was crystallized from ethyl acetate and petroleum other. It had a melting point 188-190' C.

Example 2 880 mg. of 3(a) -acetoxy-11-keto-ll-(a) -hydroutypregninehaving the structural formula:

Ha CH=CH B0 CH4 CECE AcO was hydrogenated following the same procedure as in Example 1 above. The product A Sia) -acetoxy-11 ketO-I'Hc) hydroxypregnene was crystallized from ethyl acetate and petroleum ether. It had a melting point of 188.5? to 190.5. 0.

While in the examples the starting materials were the compounds having the 3-hydroxy or the 3-acetoxy group in trans form, a compound having this group in the cis form also may be used as the steric configurations of the group in the 3 position is not important.

The temperatures mentioned in the examples are room temperatures unless otherwise indicated. The temperatures, however, are not critical and the reactions may be carried out at higher or lower temperatures: but extremely high temperatures should be avoided because the likelihood of decomposition of the desired products which may result from operation at such temperatures.

Unless otherwise stated, the reagents can be used in diflerent proportions than are indicated in the above examples as the proportion unless otherwise indicated are not critical, although enough of the reagents should be employed to insure substantially complete reaction to produce the desired products.

All melting points in this specification are cornoted The specific rotation for certain of the compounds in acetone solution for the D line of sodium is indicated hereinabove and is indicated by the symbol [11] Since certain changes in carrying out the above process. and certain modifications in the intermediates which embody the invention may be made without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted in an illustrative and not in a limiting sense.

What is claimed is:

1. A compound of the cyclopentanoperhydrophenanthrene series having the basic structural formula:

CH CB=CH CHI 1: wherein R is of the class consisting of acetyl and hydrogen.

2. A compound of the cyclopentanoperhydrophenanthrene series having the basic structural formula:

OH CH=OK| 3. n -li-acetoxy 11 keto-l'l-hydroxypreg. nene.

4. The procem that comprises hydrogenating a compound of the cyclopentanoperhydrophenanthrene series having the basic structural formula:

wherein R. is a member of the group consisting of lower aliphatic acid and hydrogen, using a catalyst selected from the group consisting of palladium, platinum, cobalt and nickel, under at. mospheric temperature and pressure whereby an equimolar quantity of hydrogen is added to the triple bond in the substituent in the 17 position to produce a. compound having the basic structural formula:

CH /CH=CH| O 5. The processvthat comprises hydrogenating a compound of the cyclopentanoperhydrophenan- .threne series having the basic structural formula:

in which R is a member of the group emulating u REFERENCES CITED The following references are of record in the me of this patent:

UNITED s'mmsm'mu'rs Number Name Date 2,266,778 Logemann Dec. 23, 1941 2,287,257 Ruzicka. Dec. 23, 1941 

